Dustry in basle



'* acid-diethylamino-ethanol ester Patented Jan. 19, 1932 UNITED STATES PATENT OFFICE KARL MIESCHER, F BASEL, SWITZERLAND, ASSIGITOR TO SOCIETY OF CHEMICAL IN- DUSTRY IN BASLE, OF BASEL, SWITZERLAND DERIVATIVES OF 4-QUINOLINE-CARBOXYLIC ACIDS No Drawing. Application filed July 11, 1928, Serial No. 292,031, and in Switzerland July 15, 1927.

acid chloride with diethylamino-ethanol, the

or 2-chloro-4-quinoline-carboxylic (Formulae I and II). The same products may also be synthesized from the sodium saltsof Q-ethox or 2-chloro4-quinoline-carboxylic acids and Q-ethoxychloroethyldiethylamine.

COgCHzCHzNUJzHQZ GO2GH2CH2N (021392 I I n When an alcoholate is caused to act upon base TI reaction occurs with elimination of halogen in the form of metal halide. For example, in the case of sodium diethyl-amind ethanol there is obtained from the base II the 2 diethylamino-ethoxyl-quinoline carb OX- ylic acid-diethylamino-ethanol ester (Formula III). In other cases an insomeric change occurs. ThuswithsodiumethylatethebaseII yields preponderatingly the Q-diethylaminoethoxy--quinoline-carboxylic acid-ethyl ester (Formula IV). The latter can also be obtainedfrom2-chlorol-quinoline-carboxylic acid-ethyl ester and sodium diethylaminoethanol.

The new compounds have Valuable therapeutic effects. 7

The following examples illustrate the invention, the parts being by weight Example 1 1 part of 2-GtllOXY-i-QtllIlOllllGC|,lbOXyllC acid-ethyl ester is boiled with an excess of diethylaminoethanol in an oil bath until no more alcohol distills. The diethylaminoethanol which has not entered into reaction is distilled in a vacuum and the residue is tak .1 up with ether, the new base extracted by means of dilute acid and then precipitated by means of sodium carbonate and extracted with ether. The 2-ethoxyl-quinoline-carboXylic acid-diethylamino-ethanol ester is a yellowish oil of boiling point 13-136 C. at 0.02 mm. pressure. In acids and in organic solvents it is freely soluble but sparingly soluble in water. Its hydrochloric melts at 186 C. with decomposition. Its hydriodide at 157 C.

The ester may also be made from chloroethyldiethylamine and sodium Q-ethoxyluinoline-carboxylate.

Example 1.2 part of diethylamino-ethanol is introduced, while cooling, into a solution of 2.3 parts of Q-chloro-quinoline-carboxylic acid chloride in toluene. The whole is heated in the water-bath and when the reaction is complete the hydrochloride of the new base is filtered. \Vhen recrystallized from alcohol it forms colorless crystals of melting point 175 C. By precipitating the aqueous solution of the hydrochloride by means of sodium carbonate the free EZ-chloro--quinolinecarboxylic acid-diethylamino-ethanol ester is obtained in the form of a yellow oil, boiling at ll0-l l- C. at 0.01 mm. pressure.

The ester may also be mane by the action of 2 molecular proportions of diethylaminoethanol on 1 molecular proportion of the acid chloride, or by the action of chloroethyldiethylainine on sodium 2-chloro-&quinolinecarboxylate.

1 part of 2--cl1loro-4-quinoline-carboxylic acid diethylamino-ethanol ester (see .Ex-

ample 2) and 05 part of sodium diethylamino-ethanol are boiled in toluene in a reflux apparatus. The new base is extracted by means of acid, precipitated from the acid solution by means of sodium carbonate and isolated in the usual manner. It is 2-diethylr amino otlroxyv l'quinoline-carboxylic aoid diethylamino-ethanol ester and is a bright yellow oil boiling at 170 C. at 0.01 mm. pressure. It is freely soluble in dilute acids and in organic solvents. Its colorless hydrochloride melts at 217 C. and dissolves freely in water and sparingly in acetone.

'lihm (fibula ester can be made directly from 1 molecular proportion of 2-chloro-4- quinoline-carboxylic acid chloride and 2 molecular proportions of sodium diethylaminoethanol.

Ewample 4 arts of 2-chlor0-4-quinoline-carboxylic acid. iethylamino-ethanol ester (see Example 2) are heated with 7 parts of sodium ethylate in toluene on the water-bath, while stirring. When the reaction is complete, the toluene solution is washed with water and extracted by means of acid. For separating from the secondarily formed di-base (Example 3.) theneutral aqueous solution may be precipitated for example by means of potassium iodide. The hydriodide of the 2- diethylamino-ethoxytquinoline carboxylic acid-53th esther thus formed is purified by recrysta lization from water; it melts at 143 C. Q'lhe free base forms bright yellow crystal'sof inelting point 36 C. It boils at C. under 0.015 mm. pressure. It is may soluble in dilute acids and in all or- ?enic solvents, but sparingly soluble in water. ts hydrochloride is colorless and melts at 162 C.

The base is also produced for example from 2,-chloro-4-quinoline-carboxylic acid ethyl ester and sodium diethylamino-ethanol according to Example 3.

analogous manner there may also be made (1) according to Example 1:

' 2-methoxy-4-quinoline-carboxylic acid-diethylamino ethanol ester, an oil boiling at 138-'1'40 C., under 0.02 mm. pressure. Its hydiodide melts at 142 C.

2-n-propyloxy-4-quinoline-carboxylic aciddi'ethylamino-ethanol ester, a yellowish oil at 146 (1., under 0.03 mm. pressure. 2- utyloxy-4-quinoline-carboxylic aciddiethylamino-ethanol ester, a yellowish oil boflii lgat C. under 0.02 mm. pressure. Its'hydriodide melts at 106 C.

Vfiisoamyloxyl-quinoline-carboxylic aciddietliylamino-ethanol ester, a yellowish oil bhfiihgaf158 C., under 0.02 mm. pressure. 2-cyclohexyloxy 4 quinoline carboxylic acid-diethylamino-ethanol ester, colorless crystals of melting point 110-111 C. after recrystallization from petroleum ether.

(2) According to Examples 3 and 4 from 2-chlorol-quinoline-carboxylic acid-diethylamino-ethanol ester the following compounds:

01 the bases 01 the salt:

-75 Muhykhnbohte. Madam crystals Hydrlodldo mouotmeltlng point 23 0. lug point 133 C. N -pronylaleol olats 0%)! mylngfilgt 154 Hyd rochlorlde m I" mm. melting point Hressure. 38 C. y -alcoho ate 0 e p n drlodide molt- .FMIIUMC. Isoemyl-alcoholate Oil of boiling point 185- Hy r odlde melt- 8O C. under 0.05 Ingpolnt124 C.

pm N-he l-alooholate 0E1 boiling point 172- W 175 C. under 0.0],

N-ootyl-sleoholate a m 5. b0 1; mt 1m 5 to 1:29 0. undo; MI pressure CycIohexy1-alcoho1- Na y colorless crystals Hydriodldo mob olme poinHl C. mg 146! C, Benzyl-aleoholaze Oil of be ng point me Hy do melt- 2w" '0.- uadar- 0.001 ulmlnt M0.

mm. pressure COQX wherein one of the letters X and Y means alkyl, alkalene, phenylalkyl or hydrophenyl and the other means which products form salts soluble in water and alcohol and have valuable therapeutic efl'ects.

2. As new products diethylamino-ethanol esters of 4-quinolinecarboxylic acids of the general formula OY N Y meaning alkyl or hydrophenyl, which products form salts soluble in water and a1- cohol and have valuable therapeutic efiects.

3. As new products diethy lamino-ethanol iodide melting at 143 (3., said product being esters of l-quinolinecarboxylic acids of the useful in therapeutics. general formula In witness whereof I have hereunto signed my name to this 27th day of June 1928.

KARL MIESCHER.

5 C OzCHgCHzN no meaning a Whole number, which products form salts soluble in water and alcohol and have valuable therapeutic effects.

4:. As a new product Q-ethoxy--quinolinecarboxylic acid-diethylamino-ethanol ester of the formula O30 GzHs CO2Y Y meaning alkyl, alkylene, phenylalkyl or hydrophenyl, which products form salts soluble in water and alcohol and have valuable therapeutic effects.

6. As new products esters of 2-diethylamino-ethory 4- quinoline-carboxylic acids of the general formula m meaning a whole number, which products form salts soluble in water and alcohol and have valuable therapeutic effects.

7. As a new product 2-diethylaminoethoxy--quinoline-carboxylic acid-ethyl ester of the formula OOgCgHs which forms bright yellow crystals of melting point 36 C. and of boiling point 135-140 C. at 0.015 mm. pressure, and is easily soluble in organic solvents and in acids, its hydro- 

